Design, Synthesis, In Silico and In Vitro Studies for New Nitric Oxide-Releasing Indomethacin Derivatives with 1,3,4-Oxadiazole-2-thiol Scaffold

Abstract

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a-p) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Moreover, their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was also performed. Based on docking results, 8k, 8l and 8m proved to be the best interaction for the COX-2 (cyclooxygense-2) target site, with an improved docking score compared with celecoxib. Referring to the thermal denaturation of serum proteins and antioxidant effects, all the tested compounds were more active than IND and aspirin, used as references. In addition, the compounds 8c, 8h, 8i, 8m, 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects.

Anti-Inflammatory Effects of Gynura procumbens on RAW264.7 Cells via Regulation of the PI3K/Akt and MAPK Signaling Pathways

“…NO is a key inflammatory mediator closely associated with the inflammatory response. Low level of NO (<300 μ M) exerts anti-inflammatory effects, while excessive NO release can intensify the process of inflammation [ 7 ]. Therefore, the inhibition of NO release becomes a crucial indicator, reflecting the anti-inflammatory activity.…”

“…Hence, any of the components or substances which can downregulate these signaling pathways and inhibit the release of inflammatory cytokines are greatly beneficial to the treatment of inflammation. Nonsteroidal anti-inflammatory drugs have been used commonly in the clinical treatment for pains and inflammations, whereas these drugs have some side effects including nausea, gastric bleeding, vomiting, and liver damage for long term use [ 2 , 7 ]. Thus, the exploitation of effective natural anti-inflammatory drugs is the focus of current research.…”

Inhibitory Potential of New Phenolic Hydrazide-Hydrazones with a Decoy Substrate Fragment towards Laccase from a Phytopathogenic Fungus: SAR and Molecular Docking Studies

“…They undergo easy dehydration to 1,3,4-oxadiazoles that present a variety of biological activities [33,34]. Hydrazide-hydrazones provide interesting properties in the field of supramolecular architecture [35][36][37][38][39], organic synthesis [33,40], chemo-and physical imaging [41][42][43][44], coordination [45][46][47][48][49], and in inorganic chemistry [50][51][52][53]. The numerous biologically active hydrazide-hydrazones are particularly worth paying attention to [54].…”

“…These are composed of carbonyl compounds linked by the hydrazine unit with carboxylic acid (RR C=N-NH-(C=O)R ) or sulfonic acids (RR C=N-NH-(SO 2 )R ) fragments [32]. They undergo easy dehydration to 1,3,4oxadiazoles that present a variety of biological activities [33,34]. Hydrazide-hydrazones provide interesting properties in the field of supramolecular architecture [35][36][37][38][39], organic synthesis [33,40], chemo-and physical imaging [41][42][43][44], coordination [45][46][47][48][49], and in inorganic chemistry [50][51][52][53].…”

Bioactive Oxadiazoles 2.0

“…The 1,3,4-oxadiazole motif, linked to a 2-sulfanylpyridine-3-carboxamide [ 1 ] or to pyrrolo[3,4-d]pyridazinone [ 2 ] was inserted into two new classes of hybrid compounds that exerted anti-inflammatory activity through selective inhibition versus cyclooxygenases (COX). Anti-inflammatory activity was also observed in indomethacin derivatives linked to the 1,3,4-oxadiazole-2-thiol scaffold with the ability to release nitric oxide [ 3 ]. The 1,3,4-isomer presented interesting bactericidal activity, which was reviewed by Glomb and Świątek [ 4 ] and was shown in newly designed 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazolines active against Staphylococcus spp.…”